Biology subjects

Tsai, L.-H.

Publications and source records attributed to Tsai, L.-H..

44 records · Page 3Linked to original sources

bioRxiv2020

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Alzheimers disease (AD) is characterized by the appearance of amyloid-{beta} plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFN{gamma}) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration. HighlightsO_LIPhosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimers disease pathologies. C_LIO_LIA phosphorylation site on Siglec-F is found to be upregulated across all three models of disease. C_LIO_LIExpression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia. C_LIO_LIOverexpression of Siglec-F and Siglec-8 in vitro drives an endocytic and pyroptotic inflammatory response. C_LI In BriefPhosphoproteome signaling changes associated with Alzheimers disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.

neuroscience↗

bioRxiv2020

Cell type-specific histone acetylation profiling of Alzheimer's Disease subjects and integration with genetics

We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimers Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) prefer to reside in the microglial histone acetylome, which varies most strongly with age. We observe acetylation differences associated with AD pathology at 3,598 peaks, predominantly in an oligodendrocyte-enriched population. Strikingly, these differences occur at the promoters of known early onset AD (EOAD) risk genes (APP, PSEN1, PSEN2, BACE1), late onset AD (LOAD) risk genes (BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1 and FERMT2), and putative enhancers annotated to other genes associated with AD pathology (MAPT). More broadly, acetylation differences in the oligodendrocyte-enriched population occur near genes in pathways for central nervous system myelination and oxidative phosphorylation. In most cases, these promoter acetylation differences are associated with differences in transcription in oligodendrocytes. Overall, we reveal deregulation of known and novel pathways in AD and highlight genomic regions as therapeutic targets in oligodendrocytes of hippocampus and dlPFC.

genetics↗

bioRxiv2020

Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration

Genomic instability caused by a deficiency in the DNA damage response and repair has been linked to age-related cognitive decline and neurodegenerative diseases. Preventing genomic instability that ultimately leads to neuronal death may provide a broadly effective strategy to protect against multiple potential genotoxic stressors. Recently, the zinc-dependent, class I histone deacetylase HDAC1 has been identified as a critical factor for protecting neurons from deleterious effects of DNA damage in Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Translating these observations to a novel neuroprotective therapy for AD, ALS, and FTD may be advanced by the identification of small molecules capable of increasing the deacetylase activity of HDAC1 selectively over other structurally similar HDACs. Here, we demonstrate that exifone, a drug previously shown to be effective in treating cognitive deficits associated with AD and Parkinsons disease, the molecular mechanism of which has remained poorly understood, potently activates the deacetylase activity of HDAC1 and provides protection against genotoxic stress. We show that exifone acts as a mixed, non-essential activator of HDAC1 that is capable of binding to both free and substrate-bound enzyme resulting in an increased relative maximal rate of HDAC1-catalyzed deacetylation. Exifone can directly bind to HDAC1 based upon biolayer interferometry assays with kinetic and selectivity profiling suggesting HDAC1 is preferentially targeted compared to other class I HDACs and the kinase CDK5 that have also been implicated in neurodegeneration. Consistent with a mechanism of deacetylase activation intracellularly, treatment of human induced pluripotent stem cell (iPSC)-derived neuronal cells resulted in globally decreased histone acetylation. Moreover, exifone treatment was neuroprotective in a tauopathy patient iPSC-derived neuronal model subject to oxidative stress. Taken together, these findings reveal exifone as a potent activator of HDAC1-mediated deacetylation, thereby offering a lead for novel therapeutic development aiming to protect genomic integrity in the context of neurodegeneration and aging. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗

bioRxiv2019

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Human brain transcriptomes can highlight biological pathways associated with Alzheimers disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 AD-associated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age- and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntingtons disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

systems biology↗

bioRxiv2018

Neutools: A collection of bioinformatics web tools for neurogenomic analysis

With a large and growing number of neurogenomic data, from epigenetic, transcriptomic to proteomic data deposited to the public domains, visualization and mining of these data alongside one own data have become extremely useful for identifying potential genetic targets and/or biological pathways to further validate and characterize in model systems. Here, a series of easy-to-use web tools (Neutools) were developed using Shiny/R codes for neuroscientists to perform basic bioinformatics data analysis and visualization. Specifically, NeuVenn calculates and plots overlap statistics for multiple input gene sets; NeuGene and NeuChIP visualize gene expression data and histone ChIP-Seq data generated from brain related tissue and cell culture, respectively. NeuVar annotates human brain GWAS variants and epigenetic features based on user-specified genes and regions. Neutools are freely available resources for all academic users to use.

bioinformatics↗

bioRxiv2018

Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain

Accumulation of tau and amyloid-{beta} are two pathologic hallmarks of Alzheimers disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-{beta}, tau protein burden had a broad effect on the epigenome, affecting 5,590 out of 26,384 H3K9Ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segments nuclear lamina association. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.

neuroscience↗

bioRxiv2017

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

Though the added value of proteomic measurements to gene expression profiling has been demonstrated, profiling of gene expression on its own remains the dominant means of understanding cellular responses to perturbation. Direct protein measurements are typically limited due to issues of cost and scale; however, the recent development of high-throughput, targeted sentinel mass spectrometry assays provides an opportunity for proteomics to contribute at a meaningful scale in high-value areas for drug development. To demonstrate the feasibility of a systematic and comprehensive library of perturbational proteomic signatures, we profiled 90 drugs (in triplicate) in six cell lines using two different proteomic assays -- one measuring global changes of epigenetic marks on histone proteins and another measuring a set of peptides reporting on the phosphoproteome -- for a total of more than 3,400 samples. This effort represents a first-of-its-kind resource for proteomics. The majority of tested drugs generated reproducible responses in both phosphosignaling and chromatin states, but we observed differences in the responses that were cell line-and assay-specific. We formalized the process of comparing response signatures within the data using a concept called connectivity, which enabled us to integrate data across cell types and assays. Furthermore, it facilitated incorporation of transcriptional signatures. Consistent connectivity among cell types revealed cellular responses that transcended cell-specific effects, while consistent connectivity among assays revealed unexpected associations between drugs that were confirmed by experimental follow-up. We further demonstrated how the resource could be leveraged against public domain external datasets to recognize therapeutic hypotheses that are consistent with ongoing clinical trials for the treatment of multiple myeloma and acute lymphocytic leukemia (ALL). These data are available for download via the Gene Expression Omnibus (accession GSE101406), and web apps for interacting with this resource are available at https://clue.io/proteomics.\n\nHighlightsO_LIFirst-of-its-kind public resource of proteomic responses to systematically administered perturbagens\nC_LIO_LIDirect proteomic profiling of phosphosignaling and chromatin states in cells for 90 drugs in six different cell lines\nC_LIO_LIExtends Connectivity Map concept to proteomic data for integration with transcriptional data\nC_LIO_LIEnables recognition of unexpected, cell type-specific activities and potential translational therapeutic opportunities\nC_LI

systems biology↗

bioRxiv2017

3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility.

Alzheimers disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (A{beta}) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of A{beta} deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to A{beta} accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early A{beta} aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt A{beta} burden. Finally, we confirm A{beta} in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to A{beta} deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.\n\nAuthor ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.\n\nRGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.\n\nHC built the custom microscope.\n\nRGC, L-HT, KC, ID wrote the manuscript.

neuroscience↗